Two new prototype microbicide products will be developed: one based on an intravaginal ring delivery system and one on a bioresponsive (smart) gel delivery vehicle. Both products will be designed to function with the following attributes: (1) extended residence in the vagina such that their use is not coitally dependent; (2) embody either single or combination anti-HIV microbicides; and (3) have favorable acceptability by women. The smart gel will spread well initially upon insertion, and then increase in physical integrity and remain in place for at least 24 hours. The intravaginal ring will deliver a constant dose of microbicide molecules continuously over a duration of one month or greater. Three new families of active ingredients will be developed and delivered by the new vehicles. These molecules target multiple steps in the HIV infection and replication pathway and include the dual acting pyrimidinediones (inhibit virus entry and reverse transcription), ISIS 5320 (inhibits CD4-gp120 mediated attachment) and the virus inactivating NCp7 inhibitors. Collectively, these active ingredients target both cell-free and cell-associated virus. Optimal formulation strategies employing either gels or rings will be designed and implemented. The proposed work scope integrates new basic science and technology, preclinical development and exploratory clinical development. The candidate novel microbicides will be optimized for activity, stability and potency against both wild type and drug-resistant viruses. Medicinal chemistry will continue to provide compounds with enhanced antiviral properties in single or combination products. The new microbicide science and technology will fill critical gaps in the field, and foster new delivery systems that are optimized with respect to vaginal deployment and drug delivery functions. Simultaneously, current knowledge and evaluation methods for acceptability of gels and rings will be expanded, and physical attributes of these vehicles will be designed to co-optimize both behavioral acceptability and biological functionality. Product development will progress in synchrony with the new scientific understanding of HIV neutralization mechanisms, delivery system biomaterials and functionality, microbicide product pharmacokinetics and pharmacodynamics, and human perception and acceptability. The set of novel new experimental methods and pharmacokinetic and pharmacodynamic models is intended to be translatable for widespread use in the microbicide pipeline.